The clinical objective in treatment of peptic ulcer disease is to decrease gastric acid secretion, based on the principle "no acid, no ulcer." Traditional peptic ulcer disease therapy involves control of diet and the use of antacids and anticholinergics.
There is evidence indicating that histamine may be the final common pathway for stimulation of gastric secretion. This effect of histamine is mediated via H.sub.2 -receptors and is not inhibited by the classical antihistamines, which are H.sub.1 -receptor blockers. A number of specific H.sub.2 -receptor blocking agents (H.sub.2 -receptor antagonists) are now known. These compounds inhibit basal acid secretion, as well as secretion by other known gastric acid stimulants, and are useful in the treatment of peptic ulcers.
Burimamide (IIa) was the first clinically effective H.sub.2 -receptor antagonist. It inhibits gastric secretion in animals and man, but oral absorption is poor.
______________________________________ ##STR4## II IIa; R.sup.6 = H, Z = CH.sub.2, X = S Burimamide b; R.sup.6 = CH.sub.3, Z = S, X = S Metiamide c; R.sup.6 = CH.sub.3, Z = S, X = NCN Cimetidine ______________________________________
Metiamide (IIb), a subsequently evaluated H.sub.2 antagonist, is more potent than burimamide and is orally active in man. Clinical utility was limited, however, owing to toxicity (agranulocytosis). Cimetidine (IIc) is as effective an H.sub.2 antagonist as metiamide, without producing agranulocytosis, and has recently been marketed as an anti-ulcer drug. The half-life of cimetidine is relatively short, thereby necessitating a therapeutic regimen of multi daily doses of 200-300 mg. tablets. There is thus a need for anti-ulcer agents which are longer acting and/or more potent than cimetidine.
Reviews on the development of H.sub.2 antagonists, including those discussed in the preceding paragraph, may be found in C. R. Ganellin, et al., Federation Proceedings, 35, 1924 (1976), in Drugs of the Future, 1, 13 (1976), and in references cited therein. Relevant patents are as follows:
Belgian Pat. No. 841,814 (Farmdoc 90568X) discloses inhibitors of histamine-stimulated gastric secretion having the formula ##STR5## in which HET is one of eight named heterocyclic rings (including imidazole) which may be substituted by (lower)alkyl, hydroxyl, amino or halogen, Z is sulfur or CH.sub.2, X is S, CHNO.sub.2, NCN or NH, Y is NH.sub.2, (lower)alkylamino, di(lower)alkylamino, (lower)alkoxy, phenylethyl, imidazolylethyl, allyl, trifluoroethyl or (CH.sub.2).sub.n R in which n is 1-12 and R is OH, (lower)alkoxy, NH.sub.2 or (lower)alkylamino; provided that, when X is NH, Y is trifluoroethyl or (CH.sub.2).sub.n R; and when X is NCN, Y may not be amino or alkylamino.
U.S. Pat. No. 4,112,234 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR6## wherein R.sup.1 is a straight or branched chain alkynyl group containing from 3 to 9 carbon atoms, and processes for the preparation thereof.
Belgian Pat. No. 843,840 (Farmdoc 05613Y) discloses histamine H.sub.2 -receptor antagonists having the formula ##STR7## wherein n is 2-3, Z is sulfur or CH.sub.2, Y is inter alia lower alkyl, and X is sulfur, CHNO.sub.2 or NCN.
U.K. Pat. No. 1,421,792 discloses H.sub.2 -receptor inhibitors of the formula ##STR8## wherein X and Y, which may be the same or different, are hydrogen, nitro, cyano or SO.sub.2 Ar, but may not both be hydrogen; R is hydrogen, (lower)alkyl or Het(CH.sub.2).sub.m Z(CH.sub.2).sub.n ; Z is sulfur or methylene; m is 0, 1 or 2 and n is 2 or 3 provided that the sum of m and n is 3 or 4; Het is an imidazole, pyridine, thiazole, isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which is optionally substituted by (lower)alkyl, hydroxy, halogen or amino; and Ar is phenyl, optionally substituted by halogen, methyl or amino.
Belgian Pat. No. 814,941 (Farmdoc 82621V) is substantially identical to U.K. Pat. No. 1,421,792, differing primarily in that the broadest definition of Het is a 5- or 6-membered nitrogen-containing ring, and that the definition of Ar is an aryl group optionally substituted by halogen, methyl or amino.
Farmdoc indicates the following U.S. Patents to be concordant with Belgian Pat. No. 814,941: 3,953,460, 4,002,759, 4,013,769, 4,024,260, 4,046,907, 4,067,984 and 4,080,459. Each of these U.S. Patents discloses as a preferred embodiment a portion of Belgian Pat. No. 841,941 and U.K. Pat. No. 1,421,792.
Belgian Pat. No. 857,388 discloses histamine H.sub.2 -receptor inhibitors of the formula ##STR9## in which R.sup.1 and R.sup.2 are the same or different and are hydrogen, (lower)alkyl, cycloalkyl, (lower)alkenyl, aralkyl or a (lower)alkyl group which is interrupted by an oxygen atom or by the group NR.sup.4 in which R.sup.4 is hydrogen or (lower)alkyl, or R.sup.1 and R.sup.2 together with the nitrogen atom form a heterocyclic ring optionally containing an oxygen atom or an NR.sup.4 group; A is (lower)alkylene; m is 2-4; n is 1 or 2, or can be zero when X is sulfur or CH.sub.2 ; X is oxygen, sulfur or CH.sub.2 ; Y is sulfur, oxygen, NR.sup.5 or CHR.sup.6 ; R.sup.5 is hydrogen, nitro, cyano, (lower)alkyl, aryl, alkylsulfonyl or arylsulfonyl; R.sup.6 is nitro, arylsulfonyl or alkylsulfonyl; and R.sup.3 is hydrogen, (lower)alkyl, (lower)alkenyl or alkoxyalkyl. This patent also discloses compounds of the formula ##STR10## wherein m and R.sup.3 are as defined above, as intermediates in the preparation of the above H.sub.2 -receptor inhibitors.
U.S. Pat. No. 4,028,379 discloses intermediates (and a process for their preparation) which are useful in the preparation of histamine H.sub.2 antagonists, said intermediates having the formula ##STR11## wherein A is (lower)alkyl and R.sub.1 is (lower)alkyl, (lower)alkoxy, 2,2,2-trifluoroethyl, (CH.sub.2).sub.n R.sub.2 or HetCH.sub.2 Z(CH.sub.2).sub.2 ; in which Het is an imidazole, thiazole, pyridine, isothiazole, oxazole, isoxazole, triazole or thiadiazole ring which is optionally substituted by (lower)alkyl, hydroxyl, (lower)alkoxy, chlorine or bromine; Z is sulfur or methylene; n is an integer of from 1 to 12; and R.sub.2 is hydroxy, (lower)alkoxy or (lower)alkylamino. The patent also discloses the use of these intermediates for the preparation of H.sub.2 antagonists of the formula ##STR12## in which R.sub.3 is (lower)alkyl, (lower)alkoxy, 2,2,2-trifluoroethyl, (CH.sub.2).sub.n R.sub.2 or HetCH.sub.2 Z(CH.sub.2).sub.2, provided that, if R.sub.1 is not HetCH.sub.2 Z(CH.sub.2).sub.2, then R.sub.3 must be HetCH.sub.2 Z(CH.sub.2).sub.2.